Work led by St. Jude Children’s Research Hospital investigators provides fresh insight into mechanisms controlling programmed cell death pathways and offers new targets in the fight against cancer and virus-infected cells
Work led by St. Jude Children’s Research Hospital scientists identified how cells flip a switch between cell survival and cell death that involves a protein called FLIP.
The findings solve a riddle that has puzzled scientists for more than a decade regarding the dual nature of caspase-8, an enzyme intimately linked to the cell’s suicide pathway but also essential for cell survival during embryonic development and the immune response. Researchers identified FLIP and the silencing of another enzyme, named RIPK3, as playing pivotal roles. The study was published in the March 2 advance online edition of Nature.
Douglas Green, Ph.D., the paper’s senior author and chair of the St. Jude Department of Immunology, said work is already underway to use the findings to generate new cancer treatment targets and fresh insight into the missteps that give rise to certain tumors as well as evidence of how some virus-infected cells escape the pathways designed to dispatch such threats.
“It is a pretty rare thing to ‘cure’ a lethal mutation in an animal by removing another gene. When that happens, the biology shouts out to us that this is important. We just have to listen,” Green said.
FLIP’s role was identified after investigators bred mice that lacked genes for both caspase-8 and RIPK3. Previous research identified RIPK3 as responsible for orchestrating cell death via programmed necrosis. Once viewed as an uncontrolled form of cell death, programmed necrosis is now recognized as a distinct form of cell suicide. The body relies on both programmed necrosis and apoptosis, the more common process, to rid itself of damaged, dangerous or unneeded cells.
While loss of caspase-8 was known to be lethal during embryonic development, in this study investigators showed mice that lacked both caspase-8 and RIPK3 were born at normal rates and appeared developmentally normal early in life.
Investigators went on to show that caspase-8 prevents programmed necrosis by combining with FLIP to form an enzyme complex that disrupts RIPK3 functioning and so prevents death via programmed necrosis. The work also demonstrated that FLIP expression prevents caspase-8 from triggering cell death via apoptosis, although the exact mechanism must still be determined. Apoptosis relies on caspase enzymes and other molecules to ensure the cell self destructs.
Green said the findings provide insight into the mechanisms at work in neuroblastoma and other tumors that suffer a loss of caspase-8. “We are beginning collaborative experiments to examine these tumors to see if RIPK3 is deleted or blocked,” he said. Neuroblastoma arises in cells of the sympathetic nervous system. It is the most common solid tumor in children, accounting for up to 10 percent of all childhood cancers.
Andrew Oberst, a St. Jude postdoctoral fellow, is the study’s first author. The other authors are Christopher Dillon, Ricardo Weinlich, Laura McCormick and Patrick Fitzgerald, all of St. Jude; Cristina Pop and Guy Salvesen, of Sanford-Burnham Medical Research Institute, La Jolla; and Razq Hakem, of the University of Toronto.
The research was supported in part by the National Institutes of Health, the Canadian Institutes of Health Research, the Sass Foundation for Medical Research and ALSAC.St. Jude Children’s Research Hospital
Founded in 1962 by the late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world, publishing more research articles than any other pediatric cancer research center in the United States. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance. St. Jude is financially supported by thousands of individual donors, organizations and corporations without which the hospital’s work would not be possible. For more information, go to www.stjude.org.St. Jude Public Relations Contacts:
Summer Freeman | Newswise Science News
Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care
Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses